NZ527051A

NZ527051A - 1-aryl-or 1-alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 ligands

Info

Publication number: NZ527051A
Application number: NZ527051A
Authority: NZ
Inventors: Ping Zhou; Michael Gerard Kelly
Original assignee: Wyeth Corp
Priority date: 2001-01-23
Filing date: 2002-01-18
Publication date: 2005-07-29
Also published as: US6509357B1; US20040087637A1; PL364568A1; AU2002251811B2; MXPA03006479A; NO20033300D0; DK1353904T3; HUP0401009A3; NO20033300L; AR034203A1; WO2002059088A1; HUP0401009A2; JP4208573B2; US20030149018A1; CN1498209A; BR0206633A; TW593278B; ATE312078T1; DE60207815T2; KR20030068591A

Abstract

Compounds of general formula I, their manufacture and uses to treat motor, anxiety, and cognitive disorders including schizophrenia, depression, Alzheimer's or Parkinson's disease. .

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 527051 WO 02/059088 5270 5 PCT/US02/01950 1-ARYL-OR 1 -ALKYLSULFONYLBENZAZOLE DERIVATIVES AS 5-HYDROXYTRYPTAMINE-6 LIGANDS This invention relates to 1-aryl- or 1-alkylsulfonylbenzazole derivatives useful as 5-hydroxytryptamine-6 ligands, to processes for preparing them, to pharmaceutical compositions containing them and to methods of treatment using them. BACKGROUND OF THE INVENTION Various central nervous system disorders such as anxiety, depression, motor disorders, etc., are believed to involve a disturbance of the neurotransmitter 5-5 hydroxytryptamine (5-HT) or serotonin. Serotonin is localized in the central and peripheral nervous systems and is known to affect many types of conditions including psychiatric disorders, motor activity, feeding behavior, sexual activity, and neuroendocrine regulation among 10 others. The effects of serotonin are regulated by the various 5-HT receptor subtypes. Known 5-HT receptors include the 5-HT1 family (e.g. 5-HT1A), the 5-HT2 family (e.g. 5-HT2A), 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 subtypes. 1 WO 02/059088 PCT/US02/01950 The recently identified human 5-hydroxytryptamine-6 (5-HT6) receptor subtype has been cloned, and the extensive distribution o,f its mRNA has been reported. Highest levels of 5-HT6 receptor mRNA have been observed 5 in the olfactory tubercle, the striatum, nucleus accumbens, dentate gyrus and CA1, CA2 and CA3 regions of the hippocampus. Lower levels of 5-HT6 receptor mRNA were seen in the granular layer of the cerebellum, several diencephalic nuclei, amygdala and in the cortex. 10 Northern blots have revealed that 5-HT6 receptor mRNA appears to be exclusively present in the brain, with little evidence for its presence in peripheral tissues. The high affinity of a number of antipsychotic agents for the 5-HT6 receptor, in addition to its mRNA localization 15 in striatum, olfactory tubercle and nucleus accumbens suggests that some of the clinical actions of these compounds may be mediated through this receptor. Therefore, 5-HT6 receptor ligands are believed to be of potential use in the treatment of certain CNS disorders 20 such as anxiety, depression, epilepsy, obsessive compulsive disorder, attention defecit disorders, migraine, cognitive memory enhancement (e.g. for the treatment of Alzheimer's disease), sleep disorders, feeding disorders (e.g. anorexia or bulimia), 25 neurodegenerative disorders (e.g. head trauma or stroke),panic attacks, withdrawal from drug abuse (e.g. cocaine, ethanol, nicotine or benzodiazepines), schizophrenia, or the like; or in the treatment of certain gastrointestinal disorders such as irritable 30 bowel syndrome. 2 WO 02/059088 PCT/US02/01950 - 3 - Therefore, it is an object of this invention to provide compounds which are useful as therapeutic agents in the treatment of a variety of central nervous system disorders related to or affected by the 5-HT6 receptor. It is another object of this invention to provide therapeutic methods and pharmaceutical compositions useful for the treatment of central nervous system disorders related to or affected by the 5-HT6 receptor. These objects should be read disjunctively with the further object of at least providing useful alternatives to known agents and therapies. It is also a feature of this invention that the compounds provided may also be used to further study and elucidate the 5-HT6 receptor. These and other objects and features of the invention will become more apparent by the detailed description set forth hereinbelow. SUMMARY OF THE INVENTION The present inveiitii©'n 'provides a compound of formula I wherein W is S02; X is CR7 or N; Y is CR8 or N with the proviso that when X is N, then Y must be CRe; Z is O, SOp or NR9; INTELLECTUAL PROPERTY OFFICE OF N.Z 15 MAR 2005 RECEIVED WO 02/059088 PCT/US02/01950 Ri and R2 are each independently H or Ci-Csalkyl; n is an integer of 2, 3 or 4; R3 and R4 are each independently H, CNR10NRnRi2 or a Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-5 C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted, or R3 and R4 may be taken together with the atom to which they are attached to form an optionally substituted 3- to 6-membered ring optionally containing an additional 10 heteroatom selected from O, N or S; R5 is H, halogen, CN, OR13, C02Ri4, CONRxsRig, CNR17NR18R19r SO2NR20R21/ SOqR22 or a Ci-C6alkyl, C2-Csalkenyl, C2-Csalkynyl, C3-C6cycloalkyl, cycloheteroalkyl, 15 phenyl or heteroaryl group each optionally substituted; m is an integer of 1, 2 or 3; p and q are each independently 0 or an integer of 1 or 2; 20 R$ is an optionally substituted Ci-Cfialkyl, aryl or heteroaryl group; R7 and Re are each independently H, halogen or a Ci-Cg alkyl, aryl, heteroaryl or Ci-Csalkoxy group each optionally substituted; 25 R9 is H or a Cx-Csalkyl, C2-C6alkenyl, C2-Csalkynyl, C3-Cscycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; Rio, R11, r12, R15; Ri6, R17, Rib and Rig are each independently H or Ci-C4alkyl; 4 WO 02/059088 PCT/US02/01950 R13 is H, COR23 or a Ci-C6alkyl, C2-C6alkenyl, C2- Csalkynylf aryl or heteroaryl group each optionally substituted; R14 is H or a Ci-Csalkyl, aryl or heteroaryl group each 5 optionally substituted; R20 and R21 are each independently H or a Ci-Csalkyl, aryl or heteroaryl group each optionally substituted; and R22 and R23 are each independently an optionally 10 substituted Ci-C6alkyl, aryl or heteroaryl group; or a pharmaceutically acceptable salt thereof. The present invention also provides methods and compositions useful for the therapeutic treatment of central nervous system disorders related to or affected 15 by the 5-HT6 receptor. DETAILED DESCRIPTION OF THE INVENTION The 5-hydroxytryptamine-6 (5-HT6) receptor is one of the most recent receptors to be identified by molecular 20 cloning. Its ability to bind a wide range of' therapeutic compounds used in psychiatry, coupled with its intriguing distribution in the brain has stimulated significant interest in new compounds which are capable of interacting with or affecting said receptor. At present, 25 there are no known fully•selective agonists. Significant efforts are being made to understand the possible role of the 5-HT6 receptor in psychiatry, cognitive dysfunction, motor function and control, memory, mood and the like. To that end, compounds which demonstrate a binding 30 affinity for the 5-HT6 receptor are earnestly sought both as an aid in the study of the 5-HT6 receptor and as 5 WO 02/059088 PCT/US02/01950 6 potential therapeutic agents in the treatment of central nervous system disorders. Surprisingly, it has now been found that 1-aryl-or 1-alkylsulfonylbenzazole derivatives of formula I demonstrate 5-HT6 affinity. Advantageously, said benzazole derivatives may be used as effective therapeutic agents for the treatment of central nervous system (CNS) disorders associated with or affected by the 5-HT6 receptor. Accordingly, the present invention provides'1-alkyl-orl-arylsulfonylbenzazole derivatives of formula-I wherein W is S02; X is CRV or N; Y is CR8 or N with the proviso that when X is N, then Y must be CR8, Z is 0, S0P or NR9; Ri and R2 are each independently H orCr-C6alkyl ; n is an integer of 2,3 or 4; R3 and R4 are each independently H, CNRi0NRnRi2, or a Cx-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted, or R3 and R4 may be taken together with the atom to which they are R3—N-CCR^^-Z (I) INTELLECTUAL PROPERTV OFFICE OF N.Z 15 MAR 2005 RECEIVED WO 02/059088 PCT/US02/01950 attached to form an optionally substituted 3- to 6-membered ring optionally containing an additional heteroatom selected from O, N or S; R5 is H, halogen, CN, ORi3, C02Ri4, CONRiSRig, 5 CNRx7NRi8R19, so2nr20r21, SOqR22 or a Ci-Cgalkyl, C2- C5alkenyl, C2-Csalkynyl, C3-C6cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted; m is an integer of 1, 2 or 3; 10 . p and q are each independently 0 or an integer of 1 or 2; Rg is an optionally substituted Ci-C6alkyl, aryl or heteroaryl group; R7 and R8 are each independently H, halogen or a Ci-Cs 15 alkyl, aryl, heteroaryl or Ci-C6alkoxy group each optionally substituted; Rg is H or a Ci-Cgalkyl, C2-Csalkenyl, C2-Cgalkynyl, C3-Cgcycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; 20 Rio, R11, R12, R15» R16 / R17, Ri8 and R19 are each independently H or Ci-C4alkyl; Ri3 is H, COR23 or a Ci-C6alkyl, C2-Cgalkenyl, C2- C6alkynyl, aryl or heteroaryl group each optionally substituted; 25 Ri4 is H or a Ci~C6alkyl, aryl or heteroaryl group each optionally substituted; R20 and R21 are each independently H or a Ci-C6alkyl, aryl or heteroaryl group each optionally substituted; and 30 R22 and R2.3 are each independently an optionally substituted Ci-Cgalkyl, aryl or heteroaryl group; or 7 WO 02/059088 PCT/US02/01950 a pharmaceutically acceptable salt thereof. As used in the specification and claims, the term halogen designates Br, CI, I or F and the term aryl denotes an aromatic hydrocarbon of 6 to 10 carbon atoms 5 such as phenyl and naphthyl. The term cycloheteroalkyl designates a 5 to 7 membered ring system containing 1 or 2 heteroatoms, which may be the same or different, selected from N, O or S and optionally containing one double bond. Exemplary of the cycloheteroalkyl ring i 10 systems included in the term as designated herein are the following rings wherein Q is NR., 0 or S; and R is H or an optional substituent as defined hereinbelow. 15 For example the term cycloheteroalkyl includes radicals derived from rings such as piperidine, morpholine, piperazine and pyrrolidine. Similarly, as used in the specification and claims, 20 the term heteroaryl designates a 5 to 10 membered aromatic ring system containing 1 or 2 heteroatoms, which may be the same or different, selected from N, 0 or S, e.g., mono- or bi-cyclic. Such heteroaryl ring systems include pyrrolyl, azolyl, oxazolyl, thiazolyl, 25 imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl, indolinyl, bensothienyl, bensofuranyl, benzisoxasolyl and 8 WO 02/059088 PCT/US02/01950 the like; the term haloalkyl designates a CnHZn+1 group having from one to 2n+l halogen atoms which may be the same or different; and the term haloalkoxy designates an 0CnH2n+i group having from one to 2n+l halogen atoms which 5 may be the same or different. In the specification and claims, when the terms Ci-C6alkyl, C2-Csalkenyl, C2-C6alkynyl, C3-C7cycloalkyl, cycloheteroalkyl, aryl or heteroaryl are designated as being optionally substituted, the substituent groups 10 which are optionally present may be one or more of those customarily employed in the development of pharmaceutical compounds or the modification of such compounds to influence their structure/activity, persistence, absorption, stability or other beneficial property. 15 Specific examples of such substituents include halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsuphinyl, alkylsulphonyl, carbamoyl, 20 alkylamido, phenyl, phenoxy, benzyl, benzyloxy, cycloheteroalkyl, heteroaryl or cycloalkyl groups, preferably halogen atoms or lower alkyl groups of 1-6 carbon atoms. Typically, 0-3 substituents may be present. When any of the foregoing substituents 25 represents or contains an alkyl substituent group, this may be linear or branched and may contain up to 12, preferably up to 6, more preferably up to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, and n- and t-butyl. 30 Pharmaceutically acceptable salts may be any acid addition salt formed by a compound of formula I and a WO 02/059088 PCT/US02/01950 pharmaceutical^ acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobroroic, citric, maleic, malonic, mandelic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluenesulfonic, methanesulfonic acid 5 or the like. Examples of R6 are phenyl, naphthyl and heteroaryl groups as illustrated above each optionally substituted by substituents as defined hereinabove. Examples of Y are N and CH. 10 Examples of X are CH and N. Ri and R2 may each represent independently for example H or methyl. An example of n is the integer 2. 15 Examples of R3 and R4 are independently H, methyl which may be substituted by substituents as herein defined, e.g. by optionally substituted phenyl such as Ci-C6alkoxyphenyl; cycloheteroalkyl having a heteroatom selected from O or S and for example having six members 20 eg pyranyl or thiopyranyl which which ring may be optionally substituted; or R3 and R4 may together with the nitrogen represent a six membered ring such as morpholinyl or piperidinyl which ring may be optionally substituted. 25 Examples of optional substituents for aryl (e.g. phenyl) or aryl substituted alkyl groups (e.g. benzyl) are halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, 30 alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsuphinyl, 10 WO 02/059088 PCT/US02/01950 alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl and benzyloxy and cycloheteroalkyl, heteroaryl cycloalkyl groups as illustrated hereinabove. 5 Preferred compounds of the invention are those compounds of formula I wherein W is S02 or CO. Also preferred are those compounds of formula I wherein Z is 0. Another group of preferred compounds of the invention are those compounds of formula I wherein n is 2. Further 10 preferred compounds of the invention are those compounds of formula I wherein R6 is an aryl or heteroaryl group each optionally substituted. More preferred compounds of the invention are those compounds of formula I wherein W is S02; Ri and R2 are H; 15 and n is 2. Another group of more preferred compounds of the invention are those compounds of formula I wherein W is S02; Z is 0; X is CR7; and R3 and R4 are taken together with the atom to which they are attached to form a 5- or 6-membered ring optionally containing one oxygen atom. 20 Among the preferred compounds of the invention are: 2-{[1-(phenylsulfonyl)-lH-indol-4-yl] oxy}ethylamine; 4-(2-morpholin-4-ylethoxy)-1-(phenylsulfonyl)-IH-indole; 1-(phenylsulfonyl)-4-(2-piperidin-l-ylethoxy)-IH-indole; N- (2-{[1-(phenylsulfonyl)-lH-indol-4-yl]oxy}ethyl)-25 tetrahydro-2H-pyran-4-amine; N,N-bis(3-methoxybenzyl)-2-{[1-(phenylsulfonyl)-lH-indol- 4-yl]oxy}ethanamine; N-(3-methoxybenzyl)-2-{[1-(phenylsulfonyl)-lH-indol-4-yl]oxy}ethanamine; 30 N,N-dimethyl-2-{[1-(phenylsulfonyl) -lH-indol-4-y1]oxy}ethanamine; 11 WO 02/059088 PCT/US02/01950 1-(phenylsulfonyl)-4-[2-(1-piperidinyl)ethoxy]-1H-indazole; 2-{[1-(phenylsulfonyl)-lH-indasol-4-yl]oxy}ethylamine; N-(2-{[1-(phenylsulfonyl)-lH-indazol-4- 5 yl]oxy}ethyl)tetrahydro-2H-pyran-4-amine; N-(2-{[1-(phenylsulfonyl)-l#-indazol-4- yl] oxy}ethyl)tetrahydro-2H-thiopyran-4-amine; 1-[(4-nitrophenyl)sulfonyl]-4-[2-(1-piperidinyl)ethoxy]-lH-indazole; 10 1-[(4-f1uoropheny1)sulfonyl]-4-[2-(1-piperidinyl)ethoxy]-lH-indasole; 4-({4-[2-(1-piperidinyl)ethoxy]-lH-indazol-1-yljsulfonyl)aniline; or a pharmaceutically acceptable salt thereof. 12 WO 02/059088 PCT/US02/01950 This invention also provides processes for preparing compounds of formula (I) which comprise one of the following: a) reacting a compound of formula (Va) hal-(CR1R2)n\Z 10 15 20 (Va) wherein hal is a halogen, e.g. chlorine or bromine and n, m, W, X, Y, Z, Ri, R2, R5 and Rs are as defined herein, with an amine of formula HNR3R4 wherein R3 and R4 are as defined herein, said reactants protected on reactive sites and/or on reactive substituent groups as required, and removing any protecting groups to give a corresponding compound of formula (I) ; or b) reducing a compound of formula (Via) 13 WO 02/059088 PCT/US02/01950 Z-tCRiRsJn-Na (Via) 5 wherein n, m, Z, W, X, Y, Ri, R2, R3, R5 and R6 are as defined herein to give a compound of formula (I) wherein R3 and R4 are both H; or 10 c) reductively alkylating a compound of formula (I) as defined herein wherein R3 and R4 are hydrogen with an alkylating agent of formula A \ /C— O B where A and B independently represent H, or optionally 15 substituted alkyl of 1-5 carbon atoms, alkenyl of 2-5 carbon atoms, alkynyl of 2-5 carbon atoms, aryl, heteroaryl or cycloheteroalkyl, or A and B together represent an optionally substituted 3-6 membered cycloalkyl or cycloheteroalkyl ring, 20 to give a compound of formula (I)wherein R3 and R4 are both methyl, or R3 is hydrogen and R4 is optionally substituted alkyl of 1-6 carbon atoms, alkenyl of 2-6 14 WO 02/059088 PCT/US02/01950 carbon atoms, alkynyl of 2-6 carbon atoms, aryl-CH2~, heteroaryl-CH2 -, cycloalkyl or cycloheteroalkyl; or 5 d) converting a compound of formula (I) having a reactive substituent group to a different compound of •c-_) formula I; or 10 e) converting a basic compound of formula (I) to an acid addition salt or vice versa. Where necessary in the processes described herein reactants may be protected on reactive sites and/or on 15 reactive substituent groups using protecting groups. Compounds of the invention may be prepared using conventional synthetic methods and, if required, standard separation and isolation techniques. For example, 20 compounds of formula I wherein W is S02, Ri and R2 are H, and 2 is 0 may be prepared by reacting an hydroxybensasole intermediate of formula II with a haloalkanol of formula III in the presence of triphenylphosphine and diethyl azodicarboxylate to give 25 the haloalkoxy derivative of formula IV; sulfonating the formula IV derivative to give the 1-sulfonylbenzazole compound of formula V; and displacing the halo group of said formula V compound with the appropriate amine to give the desired compounds of formula la. The reaction 30 sequence is illustrated in flow diagram I wherein Hal designates a halogen atom. 15 WO 02/059088 PCT/US02/01950 FLOW DIAGRAM I base y R6S02C1 (la) (V) Alternatively, compounds of formula la may be 5 prepared by reacting the intermediate of formula V with NaN3 to form the corresponding benzazolyloxyalkylazide of formula VI; reducing said formula Vl.azide with triphenylphosphine to give the formula I compound wherein Z is 0 and Rj., R2, R3 and R4 are H(Ib) ; and optionally 10 alkylating said formula lb compound to give compounds of formula la. The reactions are illustrated in flow diagram II. 16 WO 02/059088 PCT/US02/01950 FLOW DIAGRAM II (CH2)n—Hal (C.H2)n—N3 (V) NaN3 (VI) * r (la) (lb) Similarly, compounds of formula I wherein W is S02 5 and Z is S may be prepared by utilizing the appropriate benzazolylthiol starting material and employing essentially the same reaction sequences shown hereinabove in flow diagrams I and II. Compounds of formula I wherein W is S02 and Z is NH 10 (Ic) may be prepared by sulfonating a nitrobenzazole intermediate of formula VII to give the corresponding 1-sulfonyl derivative of formula VIII; reducing the formula VIII compound to give the. corresponding amine of formula IX; reacting said amine with a haloalkylaldehyde of 15 formula X to give the haloalkylamine derivative of formula XI; and displacing the halo group of said formula XI derivative with the appropriate amine to give the 17 WO 02/059088 PCT/US02/01950 desired compounds of formula Ic. The reaction sequence is shown in flow diagram III. FLOW DIAGRAM III (R5)m 1) base 2) R6S02C1 (VII) NH—(CH2)n—Hal OHC-(CH2)n.,-Hal (X) (IX) Rs I •(CH2)n—"N-R4 10 (Ic) Compounds of formula I wherein W is CO and Z is O, may be prepared by reacting a compound of formula IV with the appropriate isocyanate or carbonyl or carbamoyl halide in the presence of a base. Using these and other conventional methods, compounds of formula I may be prepared from readily available starting materials. 18 WO 02/059088 PCT/US02/01950 Advantageously, the inventive compound of formula I may be utilized in the treatment of central nervous system disorders relating to or affected by the 5-HT6 receptor such as motor, mood, psychiatric, cognitive, 5 neurodegenerative, or the like disorders. Accordingly, the present invention provides a method for the treatment of a disorder of the central nervous system (CNS) related to or affected by the 5-HT6 receptor in a patient in need thereof which comprises providing said patient a 10 therapeutically effective amount of a compound of formula I as described hereinabove. The compounds may be provided by oral or parenteral administration or in any common manner known to be an effective administration of a therapeutic agent to a patient in need thereof. 15 The therapeutically effective amount provided in the treatment of a specific CNS disorder may vary according to the specific condition(s) being treated, the size, age and response pattern of the patient, the severity of the disorder, the judgment of the attending physician and the 20 like. In general, effective amounts for daily oral administration may be about 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg and effective amounts for parenteral administration may be about 0.1 to 100 mg/kg, preferably about 0.5 to 50 mg/kg. 25 In actual practice, the compounds of the invention are provided by administering the compound or a precursor thereof in a solid or liquid form, either neat or in combination with one or more conventional pharmaceutical carriers or excipients. Accordingly, the present 30 invention provides a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I as described hereinabove. Solid carriers suitable for use in the composition 35 of the invention include one or more substances which may 19 WO 02/059088 PCT/US02/01950 also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aides, binders, tablet-disintegrating agents or encapsulating materials. In powders, the carrier may be a finely 5 divided solid which is in admixture with a finely divided compound of formula I. In tablets, the formula I compound may be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Said powders 10 and tablets may contain up to 99% by weight of the formula I compound. Solid carriers suitable for use in the composition of the invention include calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, 15 sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. Any pharmaceutically acceptable liquid carrier suitable for preparing solutions, suspensions, emulsions, syrups and elixirs may be employed in the composition of 20 the invention. Compounds of formula I may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a pharmaceutically acceptable oil or fat, or a mixture thereof. Said liquid composition may contain other 25 suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers, osmo-regulators, or the like. Examples of liquid carriers 30 suitable for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) or their 35 derivatives, or oils (e.g., fractionated coconut oil and 20 WO 02/059088 PCT/US02/01950 arachis oil). For parenteral administration the carrier may also be an oily ester such as ethyl oleate or isopropyl myristate. Compositions of the invention which are sterile 5 solutions or suspensions are suitable for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously. Inventive compositions suitable for oral administration may be in either liquid or solid composition form. 10 For a more clear understanding, and in order to illustrate the invention more clearly, specific examples thereof are set forth hereinbelow. The following examples are merely illustrative and are not to be understood as limiting the scope and underlying 15 principles of the invention in any way. Unless otherwise stated, all parts are parts by weight. The terms HPLC and NMR designate high performance liquid chromatography and nuclear magnetic resonance, respectively. The terms EtOAc and EtsO 20 designate ethyl acetate and diethyl ether, respectively. 21 WO 02/059088 PCT/US02/01950 EXAMPLE 1 Preparation of 4-(2-Chloroethoxy)-IH-indole OH 0-^C1 +h°^c1 - oq H H 5 A solution of 4-hydroxyindole (3.99 g, 30 mmol), 2-chloroethanol (6.03 ml, 90 mmol) and triphenylphosphine 10 (23.6 g, 90 mmol) in tetrahydrofuran is treated with diethyl azodicarboxylate (14.1 ml, 90 mmol) under nitrogen at room temperature, stirred for 2 hr at room temperature and concentrated in vacuo to give a residue. Cooled diethyl ether is added to the residue and the 15 solid triphenylphosphine oxide is precipitated and removed by filtration. The filtrate is concentrated and purified by flash chromatography (silica gel, EtOAc/hexane: 1.5/8.5) to give an oil. After trituration with Et20/hexane (1/10), the title compound is obtained as 20 a white solid, 4.8 g (82%) mp 60°C, identified by NMR and mass spectral analyses. 22 WO 02/059088 PCT/US02/01950 EXAMPLE 2 Preparation of 4-(2-Chloroethoxy)-1-(phenylsulfonyl)-1H-Indole A stirred solution of 4-(2-chloroethoxy)-IH-indole (3.4 g, 17.4 mmol) in tetrahydrofuran is treated with sodium hydride (60% in mineral oil, 1.04 g, 26.1 mmol) 10 under nitrogen at room temperature, stirred for 30 minutes, treated with bensenesulfonyl chloride (3.4 mL, 26.1 mmol) stirred at room temperature overnight and treated with saturated NaHC03 and EtOAc. The resultant phases are separated. The aqueous phase is extracted 15 with EtOAc and the combined organic phase is washed sequentially with H20 and saturated NaCl, dried over MgS04 and concentrated in vacuo to give a residue. The residue is purified by flash chromatography (silica gel, EtOAc/hexane: 2/8) to give the title compound as an off-20 white solid, 4.94 g (86%), mp 85-87°C, identified by NMR and mass spectral analyses. 5 23 WO 02/059088 PCT/US02/01950 EXAMPLE 3 Preparation of 2-{[1-(Phenylsulfonyl)-lH-indole-4-yl]oxy)ethylazide + NaN3 M3 5 A suspension of 4-(2-chloroethoxy)-1-(phenylsulfonyl)-1H-indole (3.35 g, 10 mmol) and sodium 10 azide (1.95 g, 30 mmol) in anhydrous dimethylformamide is stirred under nitrogen for 20 hr at 60 °C, poured into water and extracted with diethyl ether. The extracts are combined, washed sequentially with IN HCl, H20 and saturated NaCl, dried over MgS04 and concentrated in vacuo 15 to afford the title product as an off-white solid, 3.3 g (96%), identified by NMR and mass spectral analyses. EXAMPLE 4 20 Preparation of 2-f[1-(Phenylsulfonyl)-lH-indole-4-yl]oxy)ethylamine 24 WO 02/059088 PCT/US02/01950 A mixture of 2-{ [1-(phenylsulfonyl)-lH-indole-4-yl]oxyjethylazide (3.3 g, 9.6 mmol) and 5 triphenylphosphine (3.67 g, 14 mmol) in tetrahydrofuran and water is stirred under nitrogen for 24 hr at room temperature and filtered. The filtrate is concentrated in vacuo and the resultant residue is purified by flash chromatography (silica gel, EtOAc/MeOH/NH4OH: 10 8.5/1.5/0.05) to afford the title compound as an off- white solid, 2.54 g (80%), mp 71-73°C, identified by NMR and mass spectral analyses. 15 EXAMPLE 5 20 Preparation of 2-( [1-(Phenylsulfonyl)-lH-indole-4-yl] oxyMethylamine hydrochloride 0^^,NH2 qx^NH2 .HCl \ HCl rv ? _/=\ ? /==\ S°2~\_J . S02-^J> A solution of 2-{[1-(phenylsulfonyl)-lH-indole-4-yl]oxy}ethylamine (0.20 g, 0.63 mmol) in ethyl acetate is treated with HCl in diethyl ether (1M, 0.7 ml) and filtered. The filtercake is dried in vacuo to afford the 25 title product as a pink solid, 0.21 g, mp 198-200°C, identified by NMR and mass spectral analyses. 25 WO 02/059088 PCT/US02/01950 EXAMPLE 6 Preparation of N-(2-([1-(Phenylsulfonyl)-lH-indol-4-yl]oxy)ethyl)tetrahydro-2H-pyran-4-amine hydrochloride .HCl A mixture of 2-{[1-(phenylsulfonyl)-lH-indole-4-yl]oxy}ethylamine (0.316 g, 1.0 mmol), tetrahydro-4H-10 pyran-4-one (0.09 ml, 1.00 mmol) and sodium triacetoxyborohydride (0.312 g, 1.4 mmol) in 1,2-dichloroethane is treated with acetic acid (0.06 ml) at room temperature, stirred under nitrogen for 18 hr, quenched with concentrated aqueous NH4OH and diluted with 15 methylene chloride and water. The aqueous layer is separated and extracted with methylene chloride. The organic layer and extracts are combined, washed with saturated NaCl, dried over Na2S04, and concentrated in vacuo. The resultant residue is purified by flash 20 chromatography (silica gel, EtOAc/MeOH/NH4OH: 9/1/0.05) to afford the free amine of the title product as a clear oil, 0.36 g (90%). The HCl salt is prepared in HCl and ethyl acetate to give the title product as an off-white solid, mp 229-25 230°C, identified by NMR and mass spectral analyses. 26 WO 02/059088 PCT/US02/01950 EXAMPLES 7a AND 7b. 5 Preparation of (a) N,N-Bis(3-methoxybenzyl)-N-(2-f[1-(phenylsulfonyl)-lH-indol-4-yl]oxyjethylamine and (b) N- (3-methoxybenzyl) -N- (2-{ [1- (phenylsulfonyl) -1H-indol-4-yl] oxy) ethyl amine hydrochloride (a) + /0CH3 .HCl (b) 10 A mixture of 2-{[1-(phenylsulfonyl)-IH-indole-4- yl]oxy}ethylamine (0.316 g, 1.0 mmol), m-anisaldehyde (0.12 ml, 1.0 mmol) and sodium triacetoxyborohydride (0.312 g, 1.4 mmol) in 1,2-dichloroethane is treated with acetic acid (0.06 ml) at room temperature, stirred under 15 nitrogen at room temperature for 18 hr, quenched with 27 WO 02/059088 PCT/US02/01950 concentrated aqueous NH4OH and diluted with methylene chloride and water. The aqueous layer is separated and extracted with methylene chloride. The organic layer and extracts are combined and washed with saturated NaCl 5 dried over Na2S04 and concentrated in vacuo to give a residue. The residue is purified by flash chromatography (silica gel, EtOAc/MeOH/NH4OH: 9.5/0.5/0.05) to afford the free amine of 7a, 0.20 g (36%) as a clear oil and the free amine of 7b, 0.135 g (31%) as a clear oil. 10 The HCl salt of 7a is prepared in ethyl acetate and anhydrous HCl in ether to give the 7a title product as a white solid, mp 194-196°C, identified by NMR and mass spectral analyses. The HCl salt of 7b is prepared in ethyl acetate and 15 anhydrous HCl in ether to give the 7b title product as a white solid, mp 189-190°C, identified by NMR and mass spectral analyses. Example 8 20 Preparation of N,N-Dime thy 1-N-(2-{[1-phenylsulfonyl)-1H-indol-4-yl] oxy)ethylamine hydrochloride 0/^NH2 N-CH3 2 + HCH0 frv CH, .HCl 2>HC1 scvO «*-£> 25 A mixture of 2-{ [1-(phenylsulfonyl)-lH-indole-4-yl]oxy}ethylamine (0.316 g, 1.0 mmol), formaldehyde (0.16 28 WO 02/059088 PCT/US02/01950 ml, 2.0 mmol) and sodium triacetoxyborohydride (0.446 g, 2.0 mmol) in 1,2-dichloroethane is stirred under nitrogen at room temperature for 4 8 hr, quenched with concentrated aqueous NH40H and diluted with methylene chloride. The 5 aqueous layer is separated and extracted with methylene chloride. The organic layer and exti-acts are combined, washed with saturated ■ NaCl, dried over Na2S04 and concentrated in vacuo. The resultant residue is purified by -flash chromatography (silica gel, EtOAc/MeOH/NH4OH: 10 9.5/0.5/0.03) to afford the free amine as a white solid, 0.215 g (36%). The HCl salt is prepared in ethyl acetate and anhydrous HCl in ether to give the title product as a white solid, mp 140-142°C, identified by NMR and mass 15 spectral analyses. EXAMPLE 9 Preparation of 4-(2-Morpholin-4-ylethoxy)-1-(phenyl-20 sulfonyl)-1H-indole hydrochloride A mixture of 4-(2-chloroethoxy)-1-phenylsulfonyl-1H-indole (0.50 g, 1.5 mmol) and morpholine (1.30 ml, 15 mmol) in dimethylformamide (DMF) is stirred under nitrogen at 80°C for 18 hr, cooled to room temperature, 29 WO 02/059088 PCT/USO 2/01950 quenched with water and extracted with diethyl ether. The combined ether extracts are washed with saturated sodium chloride, dried over MgS04/ and concentrated in vacuo. The resultant residue is purified by flash 5 chromatography (silica gel, EtOAc/MeOH/NH4OH: 9.7/0.5/0.05) to afford the free amine as a white solid, 0.48 g (.83%) . The HCl salt is prepared in ethyl acetate and HCl to afford the title product as a white solid, mp 140-142°C, 10 identified by NMR and mass spectral analyses. EXAMPLE 10 15 Preparation of 1-(Phenylsulfonyl)-4-(2-piperidin-1-ylethoxy)-1H-indole hydrochloride A mixture of 4-(2-chloroethoxy)-1-phenylsulfonyl-1H-20 indole (0.323 g, 1.0 mmol) and piperidine (0.99 ml, 10 mmol) in dimethylformamide (DMF) is stirred under nitrogen at 8 0°C for 18 hr, cooled to room temperature, quenched with water and extracted with diethyl ether. The ether extracts are combined, washed with saturated 25 sodium chloride, dried over MgS04 and concentrated in 30 WO 02/059088 PCT/US02/01950 vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/MeOH/NH4OH: 9.7/0.5/0.05) to afford the free amine as a light yellow oil 0.34 g (88%). 5 The HCl salt is prepared in ethyl acetate and HCl to give the title product as a light yellow solid, mp 131-133°C, identified by NMR and mass spectral analyses. EXAMPLE 11 0 Preparation of 4-(2-Chloroethoxy)-lH-indazole ck-^ci 0q» Ce> I TT H COCH3 15 A stirred solution of l-acetyl-4-(2-chloroethoxy)- indasole (1.50 g, 6.3 mmol) in methanol is treated with hydrochloric acid (6.3 ml, 1.0 M HCl in Et20, 6.3 mmol) at room temperature, heated at 65°C under nitrogen for 18 hr, cooled to room temperature and concentrated in vacuo. The resultant residue is neutralized with IN NaOH (6.0 ml) and diluted with H20 and ethyl acetate. The phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water and saturated NaCl, dried over Na2S04 and concentrated in vacuo to afford the title product (1.2 g) as a yellow solid, identified by NMR and mass spectral analyses. 31 WO 02/059088 PCT/US02/01950 EXAMPLE 12 Preparation of 4-(2-Chloroethoxy)-1-(phenylsulfonyl)-1H-indazole 5 A stirred solution of 4-(2-chloroethoxy)-lH-indazole (1.1 g, 5.59 mmol) in tetrahydrofuran is treated with NaH 10 (0.335 g, 60% in mineral oil, 8.39 mmol) under nitrogen at room temperature, stirred for 3 0 minutes, treated with benzenesulfonyl chloride (0.86 ml, 6.71 mmol), stirred at room temperature for 18 hr, quenched with water and diluted with ethyl acetate. The phases are separated and 15 the organic phase is washed with water and brine, dried over MgS04 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/hexane: 3/7) to give the desired product as a white solid, 1.75 g (93%), mp 102-104°C, identified by NMR and 20 mass spectral analyses. -C1 32 WO 02/059088 PCT/US02/01950 EXAMPLE 13 Preparation of 1-Phenylsulfonyl)-4-[1-piperidinyl)ethoxy]-lH-indazole hydrochloride 5 A mixture of 4-(2-chloroethoxy)-1-(phenylsulfonyl)-lH-indasole (0.337 g, 1.0 mmol) and piperidine (0.20 ml, 10 2.0 mmol) in N,N-dimethylformamide (DMF)is stirred under nitrogen at 80°C for 18 hr, cooled, quenched with ice-water and diluted with ethyl acetate. The phases are separated. The aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with 15 water and saturated NaCl, dried over MgS04 and concentrated in vacuo to give a yellow oil residue. The residue is dissolved in ethyl acetate, treated with 1M HCl (1 ml, 1M HCl in Et20) and filtered. The filtercake is dried under vacuum to afford the title product as an 20 off-white solid, 354 mg, mp 87-89°C, identified by NMR and mass spectral analyses. 33 WO 02/059088 PCT/US02/01950 EXAMPLE 14 Preparation of 2-f [1-Phenylsulfonyl)-lH-indazol-4-y!3 oxy)ethyl amine hydrochloride 5 1) NaN3 0^^/NH2 HC1 N 3) HCl A suspension of 4-(2-chloroethoxy)-1- (phenylsulfonyl)-lH-indazole (0.66 g, 1.96 mmol) and 10 sodium aside (0.382 g, 5.87 mmol) in N,N-dimethyl- formamide is stirred under nitrogen at 60°C for 24 hr, cooled, quenched with IN HCl and extracted with ethyl acetate. The combined extracts are washed with water and saturated NaCl, dried over Na2S04 and concentrated in 15 vacuo to give a yellow solid residue. The residue is dissolved in tetrahydrofuran, treated with triphenylphosphine (0.771 g, 2.94 mmol) and water, stirred at room temperature for 18 hr and concentrated in vacuo. The resultant residue is purified by flash chromatography 20 (silica gel, EtOAc/2M NH3 in MeOH: 90/10) to give the free amine (0.41 g) as a gum. The gum is dissolved in ethyl acetate and treated with anhydrous HCl in ether. The reaction mixture is filtered and the filtercake is air-dried to give the title product as a white solid, mp 25 201-203°C, identified by NMR and mass spectral analyses. 34 WO 02/059088 PCT/US02/01950 EXAMPLES 15 and 16 Preparation of 1-(Arylsulfonyl)-4-[2-(1-piperidinyl)-ethoxy]-lH-indazole hydrochloride 5 Using essentially the same procedures described in Examples 11, 12 and 13 and employing the appropriate 10 arylsulfonyl chloride, the compounds shown in Table I are obtained and identified by NMR and mass spectral analyses. 1) HN^> Table I 15 so2r6 Ex No O, C M+H 15 4-ni tropheny1 117-119 431 16 4-fluorophenyl 122 (dec) 404 35 WO 02/059088 PCT/US02/01950 EXAMPLE 17 Preparation of N-(2-{ [1-Phenylsulfonyl)-lH-indazol-4-yl] oxyjethyl) tetrahydro-2H-pyran-4-amine 5 q/^NH2 Cc> •(>"■ Cx> ■» , /=\ ; I /=\ S03~V_^ S°2^_/ A suspension of 2-{ [1-(phenylsulfonyl)-lH-indazol-4-yl]oxy}ethylamine (0.10 g, 0.31 mmol), tetrahydro-4H-pyran-4-one (0.03 ml, 0.31 mmol) and sodium 10 triacetoxyborohydride (0.097 g, 0.43 mmol) in 1,2- dichloroethane is treated with acetic acid (0.03 ml) at room temperature, allowed to stir under nitrogen at room temperature for 18 hr, quenched with IN NaOH (2 ml) and diluted with water and a 4:1 mixture of methylene 15 chloride:isopropanol. The phases are separated and the aqueous phase is further extracted with a 4:1 mixture of methylene chloride:isopropanol. The organic phases are combined, washed with water and brine, dried over Na2S04 and concentrated in vacuo. The resultant residue is 20 dissolved in a 4:1 mixture of ethyl acetate:isopropanol, treated with anhydrous HCl in ether and filtered to obtain the title product as a white solid, mp 173-175°C, identified by NMR and mass spectral analyses. 25 36 WO 02/059088 PCT/US02/01950 EXAMPLE 18 Preparation of N- (2-f [1-Phenylsulfonyl) -lH-indaaol-4 yl] oxy)ethyl) tetrahydro-2H-thiopyran-4-ajnine 5 hydrochloride Using essentially the same procedures described in Example 17 and substituting tetrahydrothiopyran-4-one as 10 the reactant, the title product is obtained as a white solid, mp 182-184°C, identified by NMR and mass spectral analyses. A stirred solution of 1-[ (4-nitrophenyl)sulfonyl]-4-[2-(1-piperidinyl)ethoxy]IH-indasole (0.39 g, 0.91 mol) in methanol is treated with Raney Nickel followed by EXAMPLE 19 15 Preparation of 4-({4-[2-(1-Piperidinyl)ethoxy]-1H-indazol-l-yl}sulfonyl) aniline 20 37 WO 02/059088 PCT/US02/01950 hydrazine (0.2 ml, 6.3 mmol), stirred at 0°C for 2 hr and decanted. The catalyst is washed with a methanol: methylene chloride 3:7 mixture. The washes and supernatant are combined and concentrated in vacuo. The 5 resultant residue is purified by flash chromatography (silicagel, EtOAc/2M NH3 in methanol 8:2) to give the title product as a white solid, 0.15 g, mp 149-150 °C (dec), identified by NMR and mass spectral analyses. 10 EXAMPLE 20 Comparative Evaluation of 5-HT6 Binding Affinity of Test Compounds 15 The affinity of test compounds for the serotonin 5-HT6 receptor is evaluated in the following manner. Cultured Hela cells expressing human cloned 5-HT6 receptors are harvested and centrifuged at low speed 20 (1,000 x g) for 10.0 min to remove the culture media. The harvested cells are suspended in half volume of fresh physiological phosphate buffered saline solution and recentrifuged at the same speed. This operation is repeated. The collected cells are then homogenized in ten 25 volumes of 50 mM Tris.HCl (pH 7.4) and 0.5 mM EDTA. The homogenate is centrifuged at 40,000 x g for 30.0 min and the precipitate is collected. The obtained pellet is resuspended in 10 volumes of Tris.HCl buffer and recentrifuged at the same speed. The final pellet is 30 suspended in a small volume of Tris.HCl buffer and the tissue protein content is determined in aliquots of 10-25 38 WO 02/059088 PCT/US02/01950 pi volumes. Bovine Serum Albumin is used as the standard in the protein determination according to the method described in Lowry et al., J. Biol. Chem., 193:265 (1951) . The volume of the suspended cell membranes is 5 adjusted to give a tissue protein concentration of 1.0 mg/ml of suspension. The prepared membrane suspension (10 times concentrated) is aliquoted in 1.0 ml volumes and stored at -70° C until used in subsequent binding experiments. 10 Binding experiments are performed in a 96 well microtiter plate format, in a total volume of 200 pi. To each well is added the following mixture: 80.0 pi of incubation buffer made in 50 mM Tris.HCl buffer (pH 7.4) containing 10.0 mM MgCl2 and 0.5 mM EDTA and 20 pi of 15 [3H]-LSD (S.A., 86.0 Ci/mmol, available from Amersham Life Science), 3.0 nM. The dissociation constant, KD of the [3H]LSD at the human serotonin 5-HT6 receptor is 2.9 nM, as determined by saturation binding with increasing concentrations of [3H]LSD. The reaction is initiated by 20 the final addition of 100.0 pi of tissue suspension. Nonspecific binding is measured in the presence of 10.0 pM methiothepin. The test compounds are added in 20.0 pi - volume. The reaction is allowed to proceed in the dark for 25 12 0 min at room temperature, at which time, the bound ligand-receptor complex is filtered off on a 96 well unifilter with a Packard Filtermate® 196 Harvester. The bound complex caught on the filter disk is allowed to air dry and the radioactivity is measured in a Packard 30 TopCount® equipped with six phot omul tiplier detectors, after the addition of 40.0pl Microscint®-20 scintillant 39 WO 02/059088 PCT/US02/01950 to each shallow well. The unifilter plate is heat-sealed and counted in a PackardTopCount® with a tritium efficiency of 31.0%. Specific binding to the 5-HT6 receptor is defined as 5 the total radioactivity bound less the amount bound in the presence of lO.OyiM unlabeled methiothepin. Binding in the presence of varying concentrations of test compound is expressed as a percentage of specific binding in the absence of test compound. The results are plotted 10 as log % bound versus log concentration of test compound. Nonlinear regression analysis of data points with a computer assisted program Prism® yielded both the ICE0 and the Ki values of test compounds with 95% confidence limits. A linear regression line of data points is 15 plotted, from which the ICS0 value is determined and the Ki value is determined based upon the following equation: Ki = IC50 / (1 + L/Kd) where L is the concentration of the radioactive ligand 20 used and KD is the dissociation constant of the ligand for the receptor, both expressed in nM. Using this assay, the following Ki values are determined and compared to those values obtained by representative compounds known to demonstrate binding to 25 the 5-HT6 receptor. The data are shown in Table II, below. 40 WO 02/059088 PCT/US02/01950 Table II Test Compound (Ex. No.) 5 6 7a 7b 8 9 10 13 14 15 16 17 18 19 Comparative Examples 5-HT6 Binding Ki (nM) 2.0 6.0 94% @ lpM* 95% @ lpM* 4.0 92% @ lfiM* 7.0 2.0 1.0 76% @ l(lM* 19. 0 6.0 11. 0 1.0 5-HT6 Binding Ki (nM) Clozapine Loxapine Bromocriptine Methiothepin Mianserin Olanzepine 6.0 41.4 23 .0 8.3 44 .2 19.5 *% inhibition at ljxM concentration 41 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 02/059088 PCT/US02/01950 As can be seen from the results set forth above, the compounds of the present invention have a high degree of affinity for the serotonin 5-HT6 receptor. 42 - 43 - WHAT IS CLAIMED IS: X. A compound of formula X ?4 R3-N—(CR^-Z, rCr (Rs), x V L/ L. / W-R6 (I) wherein W is SO2; X is CR7 or N; Y is CRb or N with the proviso that when X is N, then Y must be CRs; Z is 0, SOp or NRs; Ri and R2 are each independently H or Ci-Cgalkyl; n is an integer of 2, 3 or 4; Ra and R4 are each independently H, CNRioNRuRm or a Ci-C6alkyl, C2-C6alkenyl, c2-C6alkynyl, c3-Cgcycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted, or R3 and R4 may be taken together with the atom to which they are attached to form an optionally substituted 3- to 6-membered ring optionally containing an additional heteroatom selected from 0, N or S; R5 is H, halogen, CN, 0Ri3, CO2R14/ CONR15R15, CNRi7NRi8Ris, SOjNR20R2i, SOqR22 or a Ci-Cgalkyl, C2~ C6alkenyl, INTELLECTUAL PROPERTY OFFICE of rj.z 15 MAR 2005 RECE IVED - 44 - C2-Cgalkynyl, C3-C6cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted; m is an integer of 1, 2 or 3; p and q are each independently 0 or an integer of 1 or 2; Rs is an optionally substituted Ci-C6alkyl, aryl or heteroaryl group; R7 and Rs are each independently H, halogen or a C1-C6 alkyl, aryl, heteroaryl or Ci-Cgalkoxy group each optionally substituted; R9 is H or a Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C$cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; Rio, R11, Ri2* Ris, R16, R17, Ri8 and R19 are each independently H or Ci-Cgalkyl,- R13 is H, CORjs or a Ci-C6alkyl, C2-C6alkenyl, C2- C«alkynyl, aryl or heteroaryl group each optionally substituted; Rn is H or a Ci-C6alkyl, aryl or heteroaryl group each optionally substituted; R2o and R2i are each independently H or a Ci-Csalkyl, aryl or heteroaryl group each optionally substituted; and R22 and R23 are each independently an optionally substituted Ci-Cgalkyl, aryl or heteroaryl group; or a pharmaceutically acceptable salt thereof. INTELLECTUAL PROPERTY OFFICE OF l\|.Z 15 MAR 2005 RECEIVED - 45 - 2. A compound according to claim 1 wherein Z is 0. 3. A compound according to claim 1 or 2 wherein n is 2. 4. A compound according to any one of claims 1 to 3 wherein Rg is an aryl or heteroaryl group each optionally substituted. 5. A compound according to any one of claims 1 to 4 wherein X is CR7 and R5 and R7 are H. 6. A compound according to any one of claims 1 to 5 wherein Ri and R2 are H. 7. A compound according to any one of claims 1 to 6 wherein R3 and R4 are taken together with the atom to which they are attached to form a 5- or 6-membered ring optionally containing one oxygen atom. 8. A compound according to claim 1 selected from the group consisting of: 2-{[1-(phenylsulfonyl)-lH-indol-4-yl]oxy)ethylamine; 4-(2-morpholin-4-ylethoxy)-1-(phenylsulfonyl)-IH-indole; 1-(phenylsulfonyl)-4-(2-piperidin-l-ylethoxy)-IH-indole; N-(2-{[1-(phenylsulfonyl)-lH-indol-4- yl]oxy}ethyl)tetrahydro-2H-pyran-4-amine; INTELLECTDAL PROPERTY OFFICE OF M.Z 15 MAR 2005 RECEIVED 46 — N,N-bis (3-methoxybenzyl) -2-1 [1- (phenylsulfonyl) -lH-indol- 4-yl]oxy}ethanamine; N-(3-methoxybenzyl)-2-{[1-(phenylsulfonyl)-lH-indol-4- yl]oxy)ethanamine; N,N-dimethyl-2-{[1-(phenylsulfonyl)-lH-indol-4-yl]oxy}ethanamine; 1- (phenylsulfonyl) -4- [2- (1-piperidinyl) ethoxy] -1H-indazole; 2-{[1-(phenylsulfonyl)-l#-indazol-4-yl]oxy)ethylamine; N~ (2- {[1-(phenylsulfonyl)-ifl-indazol-4- yl] oxyjethyl)tetrahydro-2H-pyran-4-amine; N-(2-{[1-(phenylsulfonyl)-lH-indazol-4- yl]oxy}ethyl)tetrahydro-2tf-thiopyran-4-amine,-1-[(4-nitrophenyl)sulfonyl]-4-[2-(1-piperidinyl)ethoxy] -lH-indazole;

1-[(4-fluorophenyl)sulfonyl]-4-(2-(1-piperidinyl)ethoxy] - . lH-indazole; 4-{{4-[2-(1-piperidinyl)ethoxy]-ltf-indazol-1- yl}sulfonyl)aniline; and a pharmaceutically acceptable salt thereof. 9. Use of a compound of formula I as claimed in any one of claims 1 to 8 in the preparation of a medicament for the treatment of a motor disorder, anxiety disorder or cognitive disorder. 10. Use of a compound of formula I as claimed in any ■one of claims 1 to 8 in the preparation of a medicament for the treatment of schizophrenia or depression. INTELLECTUAL PROPERTY OFFiG OP i\|.Z 2 6 APR 2255 - 47 - 11. A use according to claim 9 wherein said cognitive disorder is attention deficit disorder. 12. A use according to claim 9 wherein said cognitive disorder is Alzheimer's disease or Parkinson's disease. 13. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a compound of formula I as claimed in any one of claims 1 to 8. 14. A method for the preparation of a compound as claimed in claim 1 which comprises one of the following: a) reacting a compound of formula (Va) wherein hal is a halogen, e.g. chlorine or bromine and n, m, Wr X, Y, Z, Ri, R2r R5 and R6 are as defined in Claim 1, with an amine of formula hal- {CRiR2)--z W—R6 (Va) HNR3R4 imutc I UAL r PROPERTY (.R.,," 2 6 APR 2305 - 48 - wherein hal is a halogen, e.g. chlorine or bromine and n, m, W, X, Y, Z, Ri, R2, R5 and Rs are as defined in Claim 1, with an amine of formula hnr3r4 wherein R3 and R4 are as defined in claim 1, said reactants protected on reactive sites and/or on reactive substituent groups as required, and removing any protecting groups to give a corresponding compound of formula (I) ; or b) reducing a compound of formula (Via) Z-tCR^n-Ns w—R6 (Via) wherein n, m, Z, W, X, Y, Ri, R2, r3, R5 and R6 are as defined in claim 1 to give a compound of formula (I) wherein r3 and R4 are both H; or INTELLECTUAL PROPERTY OFFICE OF N.Z 15 MAR 2005 RECEIVED - 49 - c) reductively alkylating a compound of formula (I) as defined in Claim 1 wherein R3 and R4 hydrogen with an alkylating agent of formula a \ /C=0 b where A and B independently represent H, or optionally substituted alkyl of 1-5 carbon atoms, alkenyl of 2-5 carbon atoms, alkynyl of 2-5 carbon atoms, aryl, heteroaryl or cycloheteroalkyl, or A and B together represent an optionally substituted 3-6 membered cycloalkyl or cycloheteroalkyl ring, to give a compound of formula (I)wherein R3 and R4 are both methyl, or R3 is hydrogen and R4 is optionally substituted alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, aryl-Cfo-, heteroaryl-ch2-, cycloalkyl or cycloheteroalkyl,- or d) converting a compound of formula (I) having a reactive substituent group to a different compound of formula I; or e) converting a basic compound of formula (I) to an acid addition salt or vice versa. INTELLECTUAL PROPERTY OFFICE OF M.Z 15 MAR 2005 RECEIVED WO

02/059088 PCT/US02/01950 - 50 - 15. A compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof substantially as herein described with reference to any one or more of the Examples, excluding the 5 Comparative Examples. 16. A compound according to any one of claim 1 to 8 substantially as herein described. 10 17. Use according to claim 9 in which the compound of formula I is substantially as herein described with reference to any one or more of the Examples, excluding the Comparative Examples. 15 18. Use according to any one of claims 9 to 12 substantially as herein described. 19. A pharmaceutical composition according to claim 13 in which the compound of formula I is substantially 20 as herein described with reference to any one or more of the Examples, excluding the Comparative Examples. 20. A pharmaceutical composition according to claim 13 substantially as herein described. 25 21. A method according to claim 14 substantially as herein described with reference to any one or more of Examples 1 to 19. 30 22. A method according to claim 14 substantially as herein described. </div>